Cysteinyl leukotrienes induce nasal symptoms of allergic rhinitis via a receptor-mediated mechanism in guinea pigs.
To examine whether cysteinyl leukotrienes (cysLTs: LTC4, LTD4 and LTE4) induce symptoms of allergic rhinitis via their receptors, we studied the following: i) the specific binding of radiolabeled cysLTs to guinea pig nasal mucosa membrane and ii) effects of nasal LTD4 challenge in normal guinea pigs. The binding study indicated that there was a single population of binding sites for LTC4, LTD4 and LTE4 with Kd and Bmax values of 34.9+/-2.0, 0.252+/-0.015 and 0.589+/-0.039 nM and 10, 140+/-490, 122+/-11 and 306+/-23 fmol/mg protein, respectively. The in vivo study showed that topical nasal challenge of LTD4 (0.1-30 microg/nose) increased nasal secretion, nasal airway resistance and nasal eosinophil infiltration without inducing sneezing. While the increases in nasal secretion and nasal airway resistance were transient, peaking 10 to 20 min after LTD4 challenge, nasal eosinophil infiltration persisted at least until 24 hr post-challenge. These nasal symptoms were dose-dependently suppressed by oral administrations of pranlukast (0.3-3 mg/kg). The results suggest that cysLTs cause not only early-phase symptoms but also nasal eosinophil migration, a characteristic associated with the late-phase symptom of allergic rhinitis, via a receptor-mediated mechanism. Cysteinyl leukotrienes, thus, may be important mediators in allergic rhinitis.
Fujita
M
M
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Mishima-gun, Osaka, Japan.
Nakagawa
N
N
Yonetomi
Y
Y
Takeda
H
H
Kawabata
K
K
Ohno
H
H
D000284:Administration, Oral; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001665:Binding Sites; D002867:Chromones / Q000008:administration & dosage / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D020024:Leukotriene Antagonists; D017997:Leukotriene C4; D017998:Leukotriene D4; D017999:Leukotriene E4; D008297:Male; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism*; D018077:Receptors, Leukotriene / Q000378:metabolism*; D012221:Rhinitis, Allergic, Perennial / Q000139:chemically induced* / Q000378:metabolism; D014316:Tritium
D018927:Anti-Asthmatic Agents; D002867:Chromones; D020024:Leukotriene Antagonists; D018077:Receptors, Leukotriene; D014316:Tritium; D017997:Leukotriene C4; D017998:Leukotriene D4; D017999:Leukotriene E4; C047681:pranlukast